Biotechnology has grown into a multibillion industry with the vast majority of revenues coming from the production of transgenic proteins in recombinant hosts. To accommodate the growing demands and the continuing output of new transgenic products, many different protein production platforms have been established each with its own unique set of characteristics. Even with the vast array of available choices, many products are still limited by production costs to meet economic targets.
Plants have recently emerged as yet another production platform for protein production. Plants offer the potential advantages of 1) a non-animal source of protein reducing fears of pathogens, 2) reduced investment capital for equipment and facilities, 3) lower cost of goods, 4) rapid scale-up, 5) long term storage and transport at ambient temperatures, and 6) an alternative eukaryotic expression system that allows for posttranslational modifications (1). It is predictable that there will be certain products that may only be commercialized using the benefits that plant production systems can offer. It also seems predictable that there will not be one plant system that will be ideal for all the diverse applications of potential products.
While there are many options within plants, the need for low cost and large volumes quickly turns the focus to commodity crops. Commodity crops have been used for centuries as an excellent source of industrial and human health products as well as food and feed. For the most part, this practice has gone unnoticed by the public until the recent introduction of transgenic plants. The potential for nonfood transgenic products to be made in commodity crops has raised concerns over their intermixing with the food supply.
There are a number of approaches that can be used to reduce the risk of intermixing nonfood with food crops. The USDA has developed guidelines outlining management practices that must be followed when growing plants for nonfood uses (2). These dictate a closed loop system rather than an open system used for commodity products. The basic premises are similar to that used for other pharmaceutical production systems. The specifics vary for each crop but in general these restrictions include among others:                1. Physical isolation: food crops must not be grown in the vicinity of nonfood crops.        2. Temporal isolation: transgenic crops are delayed in the time of planting from commodity crops to reduce the possibility of out crossing.        3. Volunteer control: no food crop can be grown on the same acreage the years following the growing of the nonfood crop until all volunteers are accounted for.        4. Dedicated equipment: planting, harvesting, storage and transport equipment must not be used for food or feed crops.        5. Chain of custody: documentation accountability of the crop through its lifetime.        6. Monitoring: audit and inspection by third parties.Adherence to these guidelines will prevent inadvertent exposures but as with any system, there is always a concern that human error or natural disasters will disrupt the system and place the transgenic crop into an uncontrolled environment.        
In order to realize the benefits of plant production systems, there must be confidence that intermixing of the nonfood product with the food supply does not occur at any step in the manufacturing process. There are many steps in the process that must be addressed and most of the contamination concerns are similar to those facing non-plant host organisms for protein production. It is the potential for contamination of the seed that has raised most of the concern for plant-based protein production. Contamination could come about by unintended cross-pollination in neighboring fields of food crops, by the inadvertent spillage of seed into fields of food crops or by volunteer seed from the previous season.
All of these concerns have been addressed in USDA guidelines that outline management practices to prevent inadvertent exposure. In spite of these precautionary measures, there is still concern that as the acreage and the number of products increase, there is a greater likelihood of mishaps due to natural disasters or human error. This concern has led to a fear of using plants as a host for nonfood products which has delayed or prevented the introduction of useful products.
Keeping crops enclosed inside buildings such as greenhouses, caves, or cell culture fermentors has been proposed to alleviate some concerns associated with using field grown crops. This can be a very viable strategy for higher cost and smaller volume products. This practice, however, is not suitable for rapid scale-up or large volumes. These systems can easily raise the cost of the product well beyond practical economic restraints thereby eliminating any other advantage that may be derived using plants.
One approach previously attempted to genetically control germination has been called the “terminator technology”. This approach has already been demonstrated to work in tobacco but has been met with controversy (26) arising from the implication that growers are forced to buy new seed each year from suppliers rather then saving part of their crop from the previous season to be used as seed. This situation, however, only applies to commodity crops grown as varieties and should not be a concern for specialty-regulated crops. Moreover, it does not apply to corn which is grown as a hybrid crop and growers already buy new seed each year. Therefore, it seems reasonable that the concerns with the public perception may be eliminated regarding this specific technology with a campaign to educate the public in the new uses.
The second limitation of using terminator technology is the technical complexity of the system. This approach requires a toxin, a repressor protein, a chemically induced promoter, a recombinase system and multiple transformations of the same plant (27). While there is no reason to believe this will not work in other plants including corn, it is much more complex than inserting a single gene. This leads to a practical limitation in that it is difficult to use this routinely for new genes in discovery, adding significant time and capital to product development. It is therefore unlikely that product developers will use this system initially on nonfood products.
Another proposed solution is to use only nonfood crops for the production of transgenic nonfood products. The prospect that using a nonfood host may solve the public perception problems for plants is in contradiction to what is in practice for other non-plant hosts. There is substantial precedent in non-plant systems for safe production of nonfood products in food organisms. Examples include eggs and yeast that are routinely used to produce industrial enzymes, vaccines and therapeutics. The public has accepted this with regulatory oversight realizing that the risks are insignificant compared to the benefits. The key issue is not whether a food crop, nonfood crop or laboratory system is used to produce the transgenic protein products but rather what measures are in place to prevent inadvertent contamination of the food supply and whether the products can be produced economically.
Many of the same potential problems exist when field grown crops are used as hosts whether they are food or nonfood crops. In particular, inadvertent disposition of seed from non-food crops can result in intermixing with food crops and pose the same threat as transgenic products produced in food crops.
The use of nonfood crops also presents added safety concerns when making final products as they do not have GRAS (generally regarded as safe) status. Many nonfood plants contain toxins and carcinogens (e.g. tobacco) which need to be accounted for in the final product. The advantage of using food crops is readily apparent for such potential products as orally delivered vaccines where the final product is not purified and is taken in a processed form of the crop.
Current management practices for growing regulated transgenic crops can be expensive when factoring the cost of monitoring not only the immediate growing area but also the surrounding area for displaced seed. This could include volunteers for up to several years and miles from the initial planting, the specific time and distance determined by the specific characteristics of the crop.
One approach to containment that has proven successful with microorganisms is to have a genetically crippled host such that the organisms cannot reproduce on their own without human intervention. This has been applied to a number of different microorganisms including E. coli which has led to the use of specific strains that are used routinely in laboratory operations with minimal physical containment practices because of the confidence and experience that has been obtained over time.